ABSTRACT Diabetic retinopathy (DR) is a neurodegenerative and microvascular disorder affecting ~93 million diabetic people worldwide. The incidence of diabetes is increasing worldwide and predicted to reach ~435 million by 2045, and hence the morbidity and healthcare costs associated with DR are predicted to escalate, exacerbating an already serious public health issue. A significant problem with DR is the lack of early subjective symptoms so that by the time patients become aware of an abnormality in their vision, it is too late to reverse the disease progression. DR affects retinal neuronal tissue and breakdown of blood-retina barrier, and vascular leakage eventually causing neovascularization. The current treatments are only applicable to advanced stages of DR, which involve intraocular injection of anti-vascular endothelial growth factor (anti- VEGF) drugs and surgical laser intervention. Unfortunately, these treatments are expensive, require multiple injections and often failed to treat every patient. The long-term goal is to identify new VEGF-independent molecular targets such as S100 proteins, a family of low-molecular weight Ca2+-binding proteins implicated in a variety of intracellular and extracellular functions. Preliminary data in DR mice and porcine models showed upregulation of S100A9 protein in the retina. This proposal tests a novel hypothesis that S100A9 protein is released by the retinal microglia cells under diabetic stress, and is taken up by the endothelial cells to exacerbate inflammatory pathways in DR pathogenesis. Through three proposed aims, we will 1) define the functional role of S100A9 protein in the retinal microglia under hyperglycemia and dyslipidemia stress; 2) study the mechanistic role of S100A9 in the pathogenesis of DR; and 3) evaluate the S100A9-specific small molecule inhibitor, paquinimod for the pharmacological intervention of DR progression. These studies will lead to a better understanding of the molecular pathways and a potential novel target for the intervention of DR.